JP7366166B2 - patch - Google Patents

Description

The present invention relates to a patch.

Dimethyl sulfoxide (DMSO) is used in formulations to dissolve drugs. For example, Patent Document 1 discloses a diclofenac sodium patch using DMSO as a dissolving agent.

International Publication No. 2013/191128

Generally, the adhesiveness of a patch gradually decreases over time. The present inventors have discovered that when DMSO is blended into the adhesive layer of a patch, the composition that provides the adhesiveness to the patch becomes plasticized, and the adhesiveness of the adhesive layer decreases. Furthermore, it is important to note that if a patch containing DMSO is applied for a long time (e.g., 24 hours), sufficient adhesion may not last until the end, and the patch may peel off before the treatment is complete. The inventors found out.

The present inventors have discovered that by combining an adhesive layer containing DMSO with a support having a specific moisture permeability, the adhesion of the patch after long-term application is significantly improved, and the present invention has been developed based on this finding. It has been completed.

The adhesive patch of the present invention comprises a support layer and an adhesive layer laminated on the support layer, the support layer has a moisture permeability of 400 g/ ^m2 ·24 hours or more, and the adhesive layer , DMSO, and an adhesive. The moisture permeability of the support layer may be 750 g/m ² ·24 hours or more, or 2000 g/m ² ·24 hours or more.

The adhesive layer may include at least one adhesive selected from a rubber adhesive, an acrylic adhesive, and a silicone adhesive, and may include a styrene-isoprene-styrene block copolymer.

The drug may be one or more drugs selected from the group consisting of ketoprofen, diclofenac sodium, and indomethacin. Further, the adhesive layer may contain an organic acid.

According to the adhesive patch of the present invention, sufficient adhesion can be maintained for a long time by using a support layer having high moisture permeability. Therefore, the patch is difficult to peel off even if it is applied for a long time (for example, 24 hours). As a result, when the drug is a drug with analgesic and anti-inflammatory effects, such as ketoprofen, diclofenac sodium, or indomethacin, sufficient cumulative skin permeation is more assured when the patch is applied to the patient's skin for 24 hours. can be obtained. Moreover, the maximum plasma concentration Cmax of the drug is more reliably achieved. Therefore, the adhesive patch of the present invention enables more effective drug treatment.

2 is a graph showing the relationship between the water vapor permeability of the support layer and the rate of decrease in the mass % concentration of DMSO (hereinafter referred to as "DMSO concentration") with respect to the total mass of the adhesive layer (Test Example 1). It is a graph showing the relationship between the water vapor permeability of the support layer and the half-life of the mass % concentration of DMSO with respect to the total mass of the adhesive layer (Test Example 1).

The adhesive patch of the present invention includes a support layer and an adhesive layer laminated on the support layer. The adhesive layer is usually laminated on one side of the support layer, and if necessary, a releasable film is laminated on the other side of the adhesive layer.

First, the adhesive layer will be explained. The adhesive layer is a part that is pressed onto the skin when the patch is applied, and contains at least a drug, DMSO, and an adhesive.

The drug is a component that is soluble in DMSO. The drug may be a drug with analgesic and anti-inflammatory properties such as loxoprofen, felbinac, flurbiprofen, indomethacin, ketoprofen, and diclofenac sodium; analgesics or narcotics such as buprenorphine, fentanyl, and butorphanol; clonidine; , estradiol, tulobuterol, oxybutynin, and other drugs. The content of the drug is, for example, 1% to 20% by weight or 2% to 10% by weight based on the total weight of the adhesive layer.

DMSO dissolves the drug and improves the skin permeability of the drug, but it also causes a decrease in the tackiness of the adhesive layer. From the viewpoint of balancing these, the content of DMSO is preferably 1% by mass to 20% by mass, more preferably 1% by mass to 15% by mass, based on the total mass of the adhesive layer. , more preferably 2% to 10% by weight, particularly preferably 3% to 10% by weight.

The ratio of drug to DMSO varies depending on the drug, but for example, when diclofenac sodium is contained as a drug, the ratio of the mass of diclofenac sodium to the mass of DMSO in the adhesive layer of the patch immediately before application is equal to that of diclofenac sodium. From the viewpoint of improving skin permeability and preventing precipitation of crystals of diclofenac sodium, the ratio is preferably 1:0.3 to 1:4, more preferably 1:0.4 to 1:3. The ratio is preferably 1:0.6 to 1:3, more preferably 1:0.72 to 1:3.

The adhesive may include at least one adhesive selected from a rubber adhesive, an acrylic adhesive, and a silicone adhesive. Examples of rubber adhesives include polyisoprene, polyisobutylene (PIB), polybutadiene, styrene-butadiene-styrene block copolymer, styrene-isoprene-styrene (SIS) block copolymer, styrene-butadiene rubber, and styrene-isoprene. rubber, or a combination thereof. Among these, SIS block copolymer, PIB, or a combination thereof is preferable from the viewpoint of increasing the skin permeability of the drug and further increasing the adhesiveness of the patch. It is more preferable that there be. Examples of acrylic adhesives include (meth)acrylic acid, 2-ethylhexyl (meth)acrylate, methyl (meth)acrylate, butyl (meth)acrylate, and hydroxyethyl (meth)acrylate. This adhesive is made by polymerizing or copolymerizing at least one type of acrylic monomer. The silicone adhesive has silicone rubber such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane as a main component.

In the case of a rubber-based adhesive, the content of the adhesive is 10% by mass to 70% by mass, 10% to 40% by mass, 15% by mass, based on the total mass of the adhesive layer, from the viewpoint of adhesiveness of the patch. It may be from 15% to 35% by weight, or from 30% to 40% by weight. In the case of an acrylic adhesive or a silicone adhesive, the content of the adhesive may be 50% by mass to 90% by mass based on the total mass of the adhesive layer.

The adhesive layer may further contain an organic acid for the purpose of promoting transdermal absorption of the drug or preventing crystals of the drug from precipitating over time. Examples of organic acids include aliphatic monocarboxylic acids (formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, nonanoic acid, capric acid, lauric acid, oleic acid, linoleic acid, linolenic acid, isostearic acid, sorbic acid, pyruvic acid, etc.), aliphatic dicarboxylic acids (oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, maleic acid, fumaric acid, oxaloacetic acid, etc.), and fats. Aliphatic carboxylic acids such as tricarboxylic acids (aconitic acid, propanetricarboxylic acid, etc.), hydroxy acids (glycolic acid, lactic acid, tartronic acid, glyceric acid, hydroxybutyric acid, malic acid, tartaric acid, citric acid, isocitric acid, sugar acid, gluconic acid, glucuronic acid, ascorbic acid, erythorbic acid, etc.), aromatic carboxylic acids (benzoic acid, gallic acid, salicylic acid, acetylsalicylic acid, phthalic acid, etc.), other organic acids (mesylic acid, pesylic acid, etc.), or Examples of these salts include alkali metal salts such as sodium salts. Among these organic acids, when the drug is diclofenac sodium, citric acid, oleic acid, etc. , mesylic acid, or alkali metal salts thereof are preferred. By containing these organic acids, a sufficient amount of cumulative drug permeation through the skin can be more reliably obtained. These organic acids may be used alone or in combination of two or more. In order to improve the skin permeability of the drug and prevent the precipitation of drug crystals over time, the content of the organic acid is 0.01% by mass to 20% by mass based on the total mass of the adhesive layer. % by weight, and may be from 0.1% to 15% by weight, and from 0.2 to 13% by weight.

The adhesive layer may further contain a tackifier, a plasticizer, or other additives. The tackifier is, for example, an alicyclic saturated hydrocarbon resin, a hydrogenated rosin ester, a terpene resin, or a combination thereof. The content of the tackifier is, for example, 5% to 60% by mass, 10% to 50% by mass, 25% to 45% by mass, or 30% to 35% by mass, based on the total mass of the adhesive layer. Mass%. Plasticizers are, for example, liquid paraffin or liquid polybutene. The content of the plasticizer is, for example, 7% to 70% by weight, 10% to 60% by weight, or 11% to 25% by weight based on the total weight of the adhesive layer.

The adhesive layer may be a single layer having one type of composition, or may be a multilayer formed by laminating a plurality of layers having different compositions. The total thickness of the adhesive layer is preferably 10 μm to 1000 μm, more preferably 30 μm to 300 μm, from the viewpoint of properly adhering the patch to the skin.

The probe tack value of the adhesive layer is preferably 30 gF or more, more preferably 40 gF or more. The probe tack value of the adhesive layer may be, for example, 43 gF or more, 44 gF or more, 53 gF or more, 61 gF or more, 68 gF or more, or 71 gF or more. The higher the probe tack value, the better the adhesiveness of the patch. From the viewpoint of reducing skin irritation, the probe tack value may be 2000 gF or less, 1500 gF or less, or 1000 gF or less. In this specification, the probe tack value of the adhesive layer is measured according to the probe tack test method of ASTM D2979.

Next, the support layer will be explained. The support layer holds the adhesive layer. The moisture permeability of the support layer is 400 g/m ² ·24 hours or more. When such a support layer with high moisture permeability is used, DMSO gradually evaporates from the patch applied to the skin, improving the adhesiveness of the patch and preventing it from peeling off even if the patch is applied for a long time. Hateful. Although moisture permeability is originally an indicator of water permeability, the present inventors have found that a support with high moisture permeability also has high DMSO permeability (volatility). The moisture permeability of the support layer is, for example, 422 g/m ² for 24 hours or more, 750 g/m ² for 24 hours or more, 2000 g/m ² for 24 hours or more, 2077 g/m ² for 24 hours or more, 4000 g/m ² - It may be 24 hours or more, 5500 g/m ² · 24 hours or more, 5667 g/m ² · 24 hours or more, or 8408 g/m ² · 24 hours or more. The upper limit of moisture permeability may be 20,000 g/m ² ·24 hours. When the moisture permeability of the support layer is within this range, DMSO is more easily volatilized from the adhesive layer, and is therefore more effective in improving the adhesiveness of the patch.

The moisture permeability of the support layer in the present invention means the moisture permeability at 40° C. as defined in the JIS Z0208:1976 standard (moisture permeability testing method for moisture-proof packaging materials (cup method)).

The support layer is preferably a single layer or a laminate of fibers in the form of cloth (woven fabric, nonwoven fabric, or knitted fabric), or nonporous or porous film (sheet). The material of the support layer is polyester (such as polyethylene terephthalate (PET), polyethylene isophthalate, polypropylene terephthalate, polypropylene isophthalate, polybutylene terephthalate, or polyethylene naphthalate), polyolefin (such as ethylene, propylene, vinyl acetate, or acrylonitrile). The material is preferably one or more selected from vinyl monomer polymers or copolymers), polyamides (nylon or silk, etc.), polyurethane (PU), or cellulose (cotton, hemp, etc.). The fabric (woven fabric, nonwoven fabric, or knitted fabric) may be coated with a rubber composition. The rubber composition includes a rubber adhesive. The rubber adhesive is, for example, polyisoprene, PIB, polybutadiene, styrene-butadiene-styrene block copolymer, SIS block copolymer, styrene-butadiene rubber, styrene-isoprene rubber, or a combination thereof. The rubber composition may also include a tackifier. The tackifier is, for example, an alicyclic saturated hydrocarbon resin, a hydrogenated rosin ester, a terpene resin, or a combination thereof. Moreover, the rubber composition may further contain additives such as a plasticizer and a filler. The thickness of the support layer is, for example, 0.1 mm to 2 mm. The basis weight of the support layer is, for example, 30 g/m ² to 200 g/m ² . In this specification, the thickness and basis weight of the support layer are measured according to the standard of JIS L 1906:2000.

When the support layer is cloth-like, the 50% modulus (JIS L 1018:1999) of the support layer in both the longitudinal direction (material flow direction) and the lateral direction (material width direction) is 1N/50mm ~ Preferably it is 12N/50mm. When the 50% modulus is 12 N/50 mm or less, the stress applied to the patch due to the expansion and contraction of the skin is smaller, resulting in good adhesion to the skin.

When the support layer is a film, the material is preferably highly moisture permeable (high DMSO permeability), such as polyurethane. A film made of polyurethane is preferable because it has excellent elasticity and improves the adhesion of the patch to the skin and the ability to follow elasticity.

The support layer is preferably, for example, a nonwoven fabric or film made of polyurethane, a knitted fabric made of polyethylene terephthalate, a polyester fabric coated with a rubber composition, or a combination thereof. More specifically, the support layer is preferably a laminate of a polyurethane film and a nonwoven fabric made of polyurethane fibers, a nonwoven fabric made of PET fibers, or a polyester cloth coated with a rubber composition.

In order to prevent drug precipitation in an unused patch, the DMSO concentration in the patch immediately before application is, for example, 1% to 20% by mass, 2% to 20% by mass, based on the total mass of the adhesive layer. It may be 12% by weight, 2% to 10% by weight, or 2% to 8% by weight. Further, the DMSO concentration in the patch after being applied for 24 hours is preferably 0.1% by mass to 4% by mass, more preferably 0.1% by mass to 1.5% by mass. The support layer is preferably one that can achieve such a reduction in DMSO concentration. More specifically, when the DMSO concentration in the patch immediately before application is 2% by mass to 8% by mass, the rate of decrease in DMSO concentration is 0.08% by mass/hour to 0.16% by mass/hour (i.e., It is preferable to use a support layer in which the amount decreases by 1.92% by mass to 3.84% by mass per 24 hours. From another point of view, when the DMSO concentration in the patch immediately before application is 2% by mass to 8% by mass, the support layer preferably has a half-life of DMSO concentration of 5 hours to 24 hours. If the support layer satisfies these conditions, sufficient adhesion will tend to be maintained even after 24 hours of attachment. The rate of decrease in DMSO concentration and half-life of the above-mentioned patch were determined under conditions of 30°C and 65% RH when the patch was placed with the support layer facing upward. It is calculated by measuring the change in concentration using gas chromatography (GC).

The patch can be manufactured, for example, by the following method, but the method is not limited thereto, and any known method can be used. First, each component constituting the adhesive layer is mixed in a predetermined ratio to obtain a uniform melt. Next, the melt is applied to a predetermined thickness onto a releasable film (release film, release liner) to form an adhesive layer. Next, the support layer is pressure-bonded to the adhesive layer so that the adhesive layer is sandwiched between the release liner and the support layer. Finally, a patch can be obtained by cutting into a desired shape. In this case, the release liner is removed upon application of the patch.

(Preparation of patch)
In the examples below, unless otherwise specified, patches were prepared as follows.
1) Each component of the adhesive layer was mixed and coated on a release film (PET film subjected to mold release treatment). By drying this, DMSO was removed to a predetermined amount, and an adhesive layer (100 g/m ² ) with a thickness of 100 μm was formed.
2) A support layer was laminated on the adhesive layer to obtain a patch. The patch was cut to an appropriate size.

(Measurement of moisture permeability of support layer)
In the following examples, the moisture permeability of the support layer used was measured under the measurement conditions of 40° C. and 90% RH in accordance with JIS Z0208.

(Evaluation of adhesiveness of patch)
In the following examples, unless otherwise specified, the adhesiveness of the patch was evaluated by the following 180° peel test.
1) A 1 cm x 5 cm test piece was prepared from the patch and stored under predetermined conditions for a predetermined period of time.
2) The release film was removed from the test piece, and the test piece was attached to a stainless steel plate.
3) Using an Instron type tensile testing machine, the test piece was peeled off from the stainless steel plate in a direction of 180° at a speed of 30 cm/min, and the peeling force (gF/cm) was measured.
4) The average peeling force (gF/cm) was calculated from the integral value of the peeling force in the section showing steady peeling. High peel force means excellent adhesion.

(Evaluation of adhesiveness of patch)
In the following examples, the adhesion of the patch to the skin was evaluated by the following method. A patch was applied to the subject's skin. After 24 hours, the degree of adhesion of the patch was visually observed. The evaluation was given as "A" if 90% or more of the area of the patch was attached to the skin, and "B" in other cases.

(Test example 1)
A patch (placebo patch) having the composition shown in Table 1 was prepared. In the table, "PET film", "PET film/PET nonwoven fabric", "PU film/PU nonwoven fabric", and "PET knitted fabric" respectively refer to a film made of PET, a film made of PET, and a nonwoven fabric made of PET fibers. A laminate of a film made of PU and a nonwoven fabric made of PU fiber, and a knitted fabric made of PET. Further, the rubber adhesive in Table 1 is a mixture of an SIS block copolymer and PIB, and contains the SIS block copolymer and PIB in a mass ratio of 19:7. The "PET knitted fabric" has a moisture permeability of 5667 g/ ^m2.24 hours, a 50% modulus in the longitudinal direction of 3.9 N/50 mm, and a 50% modulus in the transverse direction of 3.4 N/50 mm. I used one (same in the example below). The patch was placed and stored in an incubator at 30° C. and 65% RH with the support layer facing upward and the release film facing downward. After 24 hours, DMSO was extracted from the patch and quantified by GC. These storage conditions simulate the environment in which the patch is applied to the skin for 24 hours.

The results are shown in Table 1, FIG. 1, and FIG. 2. The patches of Reference Examples 3 and 4 in which ^the support layer has a moisture permeability of 400 g/m ^2.24 hours or more are the patches of Reference Examples 1 and 2 in which the support layer has a moisture permeability of less than 400 g/m 2.24 hours. Compared to the patch, the DMSO concentration after 24-hour storage was significantly reduced. A relationship was observed in which the patch having a support layer with high moisture permeability had a high rate of decrease in the DMSO concentration in the adhesive layer (Figure 1) and a short half-life of the DMSO concentration (Figure 2).

In addition, the adhesiveness of the patch stored under the same conditions for 24 hours was evaluated. The results are shown in Table 1. The patches of Reference Examples 3 and 4 in which ^the support layer has a moisture permeability of 400 g/m ^2.24 hours or more are the patches of Reference Examples 1 and 2 in which the support layer has a moisture permeability of less than 400 g/m 2.24 hours. The adhesiveness (peel strength) after 24-hour storage was better than that of the patch.

Furthermore, the adhesion of the patches having the configurations shown in Table 1 after 24 hours was evaluated. The results are shown in Table 1. The patches of Reference Examples 3 and 4, in which the moisture permeability of the support layer was 400 g/m ² ·24 hours or more, had good adhesion after 24 hours of application.

(Test example 2)
A patch having the structure shown in Table 2 was prepared. The rubber adhesive in Table 2 is a mixture of SIS block copolymer and PIB, and contains the SIS block copolymer and PIB in a mass ratio of 19:7. The adhesiveness of the patches of Examples 2 and 7 to 9 was evaluated by the probe tack value measured under the following conditions according to the probe tack test method of ASTM D2979. A high probe tack value means excellent tack.
Test machine: Tacking test machine (Resca)
Probe tip material: Stainless steel Diameter of adhesive surface: 5mm
Peeling speed: 2mm/sec Adhesive load: 200gF/ ^cm2
Adhesion time: 1 second

In addition, each patch of Examples 1 to 15 and Comparative Examples 1 to 3 was applied to the lower back of a healthy adult male, and the adhesion was evaluated after 24 hours. The results are shown in Table 2. The patches of Examples 1 to 15, in which the moisture permeability of the support layer was 400 g/m ² for 24 hours or more, had good adhesion after 24 hours of application.

Furthermore, the patch of Example 2 was placed and stored in an incubator at 30° C. and 65% RH with the support layer facing upward. After 24 hours had passed, the DMSO concentration (mass %) in the adhesive layer was determined by GC, and the change in DMSO concentration was examined. The DMSO concentration after 24 hours was 1.2% by mass based on the total mass of the adhesive layer, which was 33% with respect to the initial (before storage) DMSO concentration of 100%. The rate of decrease in DMSO concentration calculated from the change in DMSO concentration was 0.1% by mass/hour, and the half-life was 15 hours.

(Test example 3)
A patch having the structure shown in Table 3 was prepared. The probe tack value of the patch having the structure shown in Table 3 was measured in the same manner as in Test Example 2, and the tackiness was evaluated. The rubber adhesive in Table 3 is a mixture of SIS block copolymer and PIB, and contains the SIS block copolymer and PIB in a mass ratio of 19:7. "Rubber/polyester fabric" in Table 3 means a polyester fabric coated with a rubber composition. The PU film in the patch of Example 16 (moisture permeability 786 g/m ² 24 hours) and the PU film in the patches of Examples 17, 19 and 20 (moisture permeability 8408 g/m ² 24 hours) were They are "3M CoTran 9701 Backing" and "3M CoTran 9700" from 3M Company.

The adhesiveness of the patches of Examples 16 to 19 and Comparative Examples 4 and 5 was evaluated after 24 hours. The results are shown in Table 3. Further, the patches of Examples and Comparative Examples were placed and stored in an incubator at 30° C. and 65% RH with the support layer facing upward. After 24 hours had passed, the DMSO concentration (mass %) in the adhesive layer was determined by GC, and the change in DMSO concentration was examined. The results are shown in Table 3. The patches of Examples 16 to 19, in which the moisture permeability of the support layer was 400 g/m ² for 24 hours or more, had good adhesion after 24 hours of application.

Claims (12)

Comprising a support layer and an adhesive layer laminated on the support layer,
The moisture permeability of the support layer is 400 g/m ² 24 hours or more,
A patch in which the adhesive layer includes a drug, dimethyl sulfoxide, and an adhesive,
The concentration of dimethyl sulfoxide immediately before application is 2% by mass to 12% by mass relative to the total mass of the adhesive layer, and the concentration of dimethyl sulfoxide after application for 24 hours is 0.0% relative to the total mass of the adhesive layer. A patch having a concentration of 1% by mass to 4% by mass. The adhesive patch according to claim 1, wherein the support layer has a moisture permeability of 750 g/m ² ·24 hours or more. The adhesive patch according to claim 1, wherein the support layer has a moisture permeability of 2000 g/m ² ·24 hours or more. The adhesive patch according to any one of claims 1 to 3, wherein the adhesive layer contains at least one adhesive selected from a rubber adhesive, an acrylic adhesive, and a silicone adhesive. The adhesive patch according to any one of claims 1 to 3, wherein the adhesive layer contains a styrene-isoprene-styrene block copolymer. The patch according to any one of claims 1 to 5, wherein the drug is one or more drugs selected from the group consisting of ketoprofen, diclofenac sodium, and indomethacin. The adhesive patch according to claim 6, wherein the adhesive layer further contains an organic acid. The adhesive patch according to any one of claims 1 to 7 , wherein the concentration of dimethyl sulfoxide immediately before application is 2% by mass to 10% by mass based on the total mass of the adhesive layer. The adhesive patch according to claim 8 , wherein the concentration of dimethyl sulfoxide immediately before application is 2% by mass to 8% by mass based on the total mass of the adhesive layer. A method for reducing the concentration of dimethyl sulfoxide in a patch, the method comprising:
The patch includes a support layer and an adhesive layer laminated on the support layer,
The adhesive layer includes a drug, dimethyl sulfoxide, and an adhesive,
The method includes using a support layer having a moisture permeability of 400 g/m ² 24 hours or more as the support layer ,
A method in which the concentration of dimethyl sulfoxide in the patch immediately before application is 2% by mass to 12% by mass based on the total mass of the adhesive layer . The method according to claim 10 , wherein the concentration of dimethyl sulfoxide in the patch after being applied for 24 hours is 0.1% by mass to 4% by mass based on the total mass of the adhesive layer. The method according to claim 10 or 11 , wherein the adhesive layer further contains an organic acid.

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